The separation of the enantiomers of an acid or a base or the formation of a salt with an optically active base or acid respectively is an elementary knowledge in the art.
On the contrary, there are no further generally applicable pieces of information which allow the chemist to anticipate what are the critical conditions which allow one to separate the enantiomers of a given acid or of a given base on an industrial scale in the most economical way. The finding of these conditions is a largely empirical science which involves overcoming technical prejudices and the original solution of specific technical problems.
The parameters which must be taken into consideration for evaluating if a process of optical resolution is economical on industrial scale are the following:
1. optical purity of the obtained product; PA1 2. yield of the optically active product; PA1 3. productivity (employed volume/amount of treated product ratio); PA1 4. cost of the resolving agent which is used; PA1 5. recoverability of the resolving agent which is used; PA1 6. cost of the recovery of the resolving agent which is used; PA1 7. cost of the solvent or of the solvents mixture which is used; PA1 8. recoverability of the solvent(s) which is (are) used; PA1 9. cost of the recovery of the solvent(s) which is (are) used.
Because of the large therapeutic importance of Naproxen, many methods have been suggested until now for separating the optical isomers of (.+-.) AMNP with optically active bases.
Phenylethylamine or PEA is indicated in some known publications as one of the optically active bases which may be used for separating (.+-.) AMNP.
Among these publications, those which do not indicate the experimental conditions represent information devoid of any value to the artisan.
On the contrary, those which indicate specific operative conditions do not offer such an advantage as to encourage further investigations.
In U.K. Patent Specification No. 1,296,493, PEA is mentioned in generic terms as one of the many optical active bases which may be used for separating (.+-.) AMNP but there is no suggestion concerning the proper solvent, the specific operative conditions, the optical purity of the thus obtained product, the productivity of the process or the recoverability of the solvent and/or of PEA.
U.S. Pat. No. 4,209,638 discloses a process for increasing the amount of a desired enantiomer in a racemic mixture of an arylpropionic acid. (.+-.) AMNP and PEA are mentioned among the possible acids and bases, respectively. The solvent used is a petroleum fraction which begins to boil at 112.degree. C. In accordance with the aim of the patent, an AMNP is obtained which is only slightly enriched with respect to (.+-.) enantiomer and the specification does not mention what kind of and how many further treatments are necessary to obtain a product having the desired optical purity.
European Patent Application No. 82200512.0 discloses a process wherein the resolution with PEA is carried out in water. This process has an unfavourable low productivity (solvent/substrate ratio about 17) and requires repeated crystallizations before obtaining a product having the required optical purity.
Japanese non-examined application No. 50/55,135 conjectures the use of many solvents, inclusive of chloroform, and of a quantity of PEA from 0.5 to 1 mole with respect to one mole of (.+-.) AMNP but it indicates as preferred conditions the use of a mixture of methyl alcohol and ethyl acetate, as solvent, and of one mole of PEA for each mole of (.+-.) AMNP. With this conditions the productivity is about 13 and the yield of (+) AMNP having an optical rotatory power of +66.0 (c=1%, chloroform) is only 48% whereas the yield of AMNP having an optical rotatory power of +63.4 is only 56%.
Furthermore, the artisan appreciates immediately the disadvantages connected with the recovery of the solvents. PEA and (-) AMNP. In fact, (-) AMNP and PEA can not be recovered from the mother liquors by simple addition of acids or bases until they contain methanol; on the other hand the removal of the latter, by distillation, from the mother liquors involves also the removal of ethyl acetate because their boiling points are very close and they form an azeotropic mixture. It is therefore self-evident that the low productivity, low yield and high recovery costs do not make this process economical on an industrial scale. Furthermore, the fact that in this patent application is pointing out these conditions as the best ones discourages the technician from investigating all the other innumerable conditions which are mentioned in generic terms in the Japanese Patent Application No. 50/55,135.
Finally, it is known in the art that the maximum resolving power is usually reached when 1 mole of optical active base is used for each mole of racemic acid or, when using a less optically active base, by completing the salt formation by adding another base.